Effects of L-citrulline Supplementation on Vascular Function in Metabolic Syndrome

• ClinicalTrials.gov Identifier: NCT06025357
• Recruitment Status: Recruiting
• First Posted: September 6, 2023
• Last Update Posted: September 6, 2023
• Sponsor: Texas Tech University
• Information provided by (Responsible Party): Arturo Figueroa, Texas Tech University

Study Description

Brief Summary:

The objective of this project is to provide evidence that L-Citrulline (CIT) supplementation can improve vascular function in the fasted and acute hyperglycemia conditions in middle-aged and older women with metabolic syndrome.

Condition or disease	Intervention/treatment	Phase
Metabolic Syndrome; Menopause	Dietary Supplement: L-Citrulline supplementation; Dietary Supplement: Placebo	Not Applicable

Detailed Description:

Using a double-blind, randomized, placebo-controlled, and parallel design, middle-aged and older women with metabolic syndrome will be randomized into receiving either CIT supplementation (10g/day) or placebo (Microcrystalline Cellulose) for 4 weeks.

The first visit will be approximately 1hr and 30 minutes. The 2nd and 3rd visits will each be approximately 2hrs and 30 minutes, separated by 4 weeks in between each visit. During visits 2 and 3, vascular measurements will be assessed in the fasted state and 30, 60, and 90 minutes after acute glucose ingestion (75g).

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Parallel Assignment Double (Participant, Investigator) Randomized, double-blind, placebo-controlled, parallel study design
• Masking: Double (Participant, Investigator)
• Primary Purpose: Basic Science
• Official Title: Effects of L-Citrulline Supplementation on Vascular Function During Fasted and Acute Hyperglycemia in Middle-aged and Older Women With Metabolic Syndrome
• Actual Study Start Date: January 1, 2023
• Estimated Primary Completion Date: May 1, 2024
• Estimated Study Completion Date: August 1, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: L-citrulline; L-citrulline: 10 grams/day	Dietary Supplement: L-Citrulline supplementation; 4 weeks of L-Citrulline supplementation (10 grams/day).
Experimental: Placebo; Microcrystalline Cellulose	Dietary Supplement: Placebo; 4 weeks of microcrystalline Cellulose supplementation.

Outcome Measures

Primary Outcome Measures :

1. Macrovascular Endothelial function in the fasted condition [ Time Frame: 4 weeks ]
   Endothelial function will be measured via brachial artery flow mediated dilation (ultrasonography) during reactive hyperemia at baseline and after 4 weeks of supplementation.
2. Microvascular endothelial function in the fasted condition [ Time Frame: 4 weeks ]
   Endothelial function will be measured using forearm muscle oxygenation (near-infrared spectroscopy) will assessed during reactive hyperemia at baseline and after 4 weeks of supplementation.
3. Microvascular digital endothelial function in the fasted condition [ Time Frame: 4 weeks ]
   Endothelial function will be measured using peripheral (finger) arterial tonometry (EndoPAT device) during reactive hyperemia at baseline and after 4 weeks of supplementation.
4. Macrovascular Endothelial function during acute hyperglycemia [ Time Frame: 4 weeks ]
   Endothelial function will be measured via brachial artery flow mediated dilation (ultrasonography) during reactive hyperemia at 30, 60, and 90 minutes after oral glucose ingestion at baseline and after 4 weeks of supplementation.
5. Microvascular forearm endothelial function during acute hyperglycemia [ Time Frame: 4 weeks ]
   Endothelial function will be measured using forearm muscle oxygenation (near-infrared spectroscopy) during reactive hyperemia at 30, 60, and 90 minutes after oral glucose ingestion at baseline and after 4 weeks of supplementation.
6. Central and peripheral arterial stiffness in the fasted condition [ Time Frame: 4 weeks ]
   Arterial stiffness will be measured using central (carotid-femoral) and peripheral (femoral-ankle) PWV at baseline and after 4 weeks of supplementation.
7. Central arterial stiffness during acute hyperglycemia [ Time Frame: 4 weeks ]
   Arterial stiffness will be measured using central (carotid-femoral) PWV at 30, 60, and 90 minutes after oral glucose ingestion at baseline and after 4 weeks of supplementation.
8. Blood pressure in the fasted condition [ Time Frame: 4 weeks ]
   Brachial and aortic blood pressures will be assessed using an automated sphygmomanometry arm cuff (SphygmoCor XCEL). Beat-to-beat blood pressure will be measured using an automated photoplethysmography finger cuff (Fineometer). Blood pressure will be measured at baseline and after 4 weeks of supplementation.
9. Blood pressure during acute hyperglycemia [ Time Frame: 4 weeks ]
   Brachial and aortic blood pressures (systolic and diastolic) will be assessed using an automated sphygmomanometry arm cuff (SphygmoCor XCEL). Beat-to-beat blood pressure will be measured using an automated photoplethysmography finger cuff (Fineometer). Blood pressure will be measured after an oral glucose ingestion at 30, 60, and 90 minutes at baseline and after 4 weeks of supplementation.
10. Total peripheral resistance in the fasted condition. [ Time Frame: 4 weeks ]
    Total peripheral resistance will be measured using an automated photoplethysmography finger cuff (Finometer) at baseline and after 4 weeks of supplementation.
11. Total peripheral resistance during acute hyperglycemia [ Time Frame: 4 weeks ]
    Total peripheral resistance will be measured using an automated photoplethysmography finger cuff (Finometer) at 30, 60, and 90 minutes after oral glucose ingestion at baseline and after 4 weeks of supplementation.
12. Stroke volume in the fasted condition [ Time Frame: 4 weeks ]
    Stroke volume will be measured using an automated photoplethysmography finger cuff (Finometer) at baseline and after 4 weeks of supplementation.
13. Stroke volume during acute hyperglycemia [ Time Frame: 4 weeks ]
    Stroke volume will be measured using an automated photoplethysmography finger cuff (Finometer) at 30, 60, and 90 minutes after oral glucose ingestion at baseline and after 4 weeks of supplementation.
14. 24-hour ambulatory blood pressure monitoring [ Time Frame: 4 weeks ]
    An ambulatory blood pressure cuff, measuring blood pressure for 24-hours will be obtained on two separate days at baseline and after 4 weeks of supplementation.

Secondary Outcome Measures :

1. Serum glucose and insulin levels. [ Time Frame: 4 weeks ]
   Serum glucose and insulin levels will be tested at baseline and after 4 weeks of supplementation.
2. Serum arginine levels [ Time Frame: 4 weeks ]
   Serum L-Arginine levels will be tested at baseline and after 4 weeks of supplementation.
3. Serum arginase levels [ Time Frame: 4 weeks ]
   Serum arginase levels will be tested at baseline and after 4 weeks of supplementation.
4. Serum Nitric Oxide levels [ Time Frame: 4 weeks ]
   Serum nitric oxide levels will be tested at baseline and after 4 weeks of supplementation.
5. Serum Endothelin-1 levels [ Time Frame: 4 weeks ]
   Serum endothelin-1 levels will be tested at baseline and after 4 weeks of supplementation.

Eligibility Criteria

• Ages Eligible for Study: 45 Years to 79 Years (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

Must present at least 3 of the following 5 cardiometabolic risk factors

• Waist circumference ≥88 cm
• Fasting glucose between 100-125 mg/dL or HbA1c between 5.7-6.4%.
• Blood pressure ≥130 mm Hg
• Triglyceride ≥ 150 mg/dL
• HDL <50 mg/dL

The following are also inclusion criteria's:

• Women aged 45-79 years old
• Body mass index ≤ 39.9 kg/m2
• Sedentary (defined as < 120 min/week of exercise)
• Abstain from any dietary supplements with vascular effects for one month prior to the beginning of the study and until participation in study has terminated.

Exclusion Criteria:

• < 45 and > 79 years of age
• Use of medications and/or any supplements that may affect outcome variables (such as arginine-containing supplements, nitroglycerin, statin drugs, biguanides, insulin, beta blockers, statins, verapamil)
• Systolic blood pressure ≥ 160 mmHg
• BMI > 40 kg/m2
• Recent changes in medication (3 months)
• Current smoking any tobacco use
• Cardiovascular disease, diabetes (Type 1 or 2), and other metabolic or chronic diseases
• More than 7 alcoholic drinks/week of consumption

Contacts and Locations

Contacts

Contact: Arturo Figueroa, Ph.D,MD; 806-834-5587; arturo.figueroa@ttu.edu

Locations

United States, Texas

TTU Kinesiology and Sport Management Building; Recruiting

Lubbock, Texas, United States, 79409

Contact: Arturo Figueroa, M.D., Ph.D. 806-834-5587

Sponsors and Collaborators

Texas Tech University

Investigators

• Principal Investigator: Arturo Figueroa; Texas Tech University

More Information

Publications of Results:

Maharaj A, Fischer SM, Dillon KN, Kang Y, Martinez MA, Figueroa A. Effects of L-Citrulline Supplementation on Endothelial Function and Blood Pressure in Hypertensive Postmenopausal Women. Nutrients. 2022 Oct 20;14(20):4396. doi: 10.3390/nu14204396.

Other Publications:

Figueroa A, Maharaj A, Kang Y, Dillon KN, Martinez MA, Morita M, Nogimura D, Fischer SM. Combined Citrulline and Glutathione Supplementation Improves Endothelial Function and Blood Pressure Reactivity in Postmenopausal Women. Nutrients. 2023 Mar 23;15(7):1557. doi: 10.3390/nu15071557.

Maharaj A, Fischer SM, Dillon KN, Kang Y, Martinez MA, Figueroa A. Acute Citrulline Blunts Aortic Systolic Pressure during Exercise and Sympathoactivation in Hypertensive Postmenopausal Women. Med Sci Sports Exerc. 2022 May 1;54(5):761-768. doi: 10.1249/MSS.0000000000002848. Epub 2022 Jan 3.

McDonald JD, Mah E, Chitchumroonchokchai C, Dey P, Labyk AN, Villamena FA, Volek JS, Bruno RS. Dairy milk proteins attenuate hyperglycemia-induced impairments in vascular endothelial function in adults with prediabetes by limiting increases in glycemia and oxidative stress that reduce nitric oxide bioavailability. J Nutr Biochem. 2019 Jan;63:165-176. doi: 10.1016/j.jnutbio.2018.09.018. Epub 2018 Sep 25.

Figueroa A, Alvarez-Alvarado S, Ormsbee MJ, Madzima TA, Campbell JC, Wong A. Impact of L-citrulline supplementation and whole-body vibration training on arterial stiffness and leg muscle function in obese postmenopausal women with high blood pressure. Exp Gerontol. 2015 Mar;63:35-40. doi: 10.1016/j.exger.2015.01.046. Epub 2015 Jan 28.

• Responsible Party: Arturo Figueroa, Arturo Figueroa, Principal Investigator, Texas Tech University
• ClinicalTrials.gov Identifier: NCT06025357
• Other Study ID Numbers: IRB2022-362
• First Posted: September 6, 2023
• Last Update Posted: September 6, 2023
• Last Verified: August 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Arturo Figueroa, Texas Tech University:

Endothelial function; Aortic Hemodynamics; Blood pressure; Obesity; Hypertension

Additional relevant MeSH terms:

Metabolic Syndrome; Syndrome; Disease; Pathologic Processes; Insulin Resistance; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases